Halogenated organic compounds play a central role in organic chemistry, affording important components of a variety of biologically active molecules as well as pharmacologically active agents. Alkyl chlorides also find widespread use as intermediates in organic synthesis, as in cross-coupling reactions.
Manganese porphyrins and Schiff base complexes have long been known to be effective catalysts for the oxygenation of both unsaturated and saturated hydrocarbons. Nearly all of the advances in the field dealt with oxygenation reactions, particularly olefin epoxidation and alkane hydroxylation. Small amounts of halogenation were described in the original reports. However, most of these reactions resulted in poor selectivity for non-oxygen functionalization, since competitive oxygenation of substrates remains the main reaction. High selectivity of chlorination has been reported by Ricci et al. in the nickel(salen)/hypochlorite system, but the substrate scope was limited and the reaction was likely propagated by chloroxy radical. (Querci, C.; Strologo, S.; Ricci, M. Tetrahedron Lett. 1990, 31, 6577-6580, which is incorporated herein by reference as if fully set forth). There are at present few if any ways to incorporate halogen atoms selectively into complex compounds.
Nature has found highly selective ways to transform aliphatic C—H bonds into alcohols, halides and olefins using reactive metal-oxo intermediates within enzymes. A notable exception is aliphatic fluorination, for which there are no known biochemical precedents. There are also no direct ways to convert unreactive sp3 C—H bonds into C—F bonds through chemical catalysis.
Although strategies for aromatic C—H fluorination developed over the past five years have provided novel and unprecedented access to complex aryl fluorides, (Furuya, T.; Kamlet, A. S.; Ritter, T., Catalysis for Fluorination and Trifluoromethylation Nature 2011, 473, 470-477; P. P. Tang, T. Furuya, T. Ritter, J Am Chem Soc 132, 12150 (2010); and D. A. Watson et al. Science 325, 1661 (2009), which are incorporated herein by reference as if fully set forth) there is a notable lack of recent progress for the catalytic fluorination of aliphatic C—H bonds (P. Herrmann, J. Kvicala, V. Pouzar, H. Chodounska, Collect Czech Chem C 73, 1825 (2008); and Rozen, S.; Gal, C., Activating Unreactive Sites of Organic-Molecules Using Elemental Fluorine, J. Org. Chem. 1987, 52, 2769-2779, which are incorporated herein by reference as if fully set forth). Traditional methods for introducing fluorine into a saturated framework require harsh conditions and highly toxic fluorine sources, such as elemental fluorine, that require specialized equipment and are not compatible with many typical substituents and functional groups (R. D. Chambers, A. M. Kenwright, M. Parsons, G. Sandford, J. S. Moilliet, J Chem Soc Perk T 1, 2190 (2002); S. Rozen. Eur. J. Org. Chem., 2433 (2005); and S. Rozen. Acc. Chem. Res. 38, 803 (2005), which are incorporated herein by reference as if fully set forth). Metal catalyzed direct benzylic C—H fluorination has been achieved recently with palladium catalysts and a source of “F+” (K. L. Hull, W. Q. Anani, M. S. Sanford. J. Am. Chem. Soc. 128, 7134 (2006); X. S. Wang, T. S. Mei, J. Q. Yu. J. Am. Chem. Soc. 131, 7520 (2009); T. D. Beeson, D. W. C. MacMillan. J. Am. Chem. Soc. 127, 8826 (2005), which are incorporated herein by reference as if fully set forth). Also, advances in the field of enantioselective organocatalytic fluorination have been reported that are capable of introducing a fluorine atom adjacent to a carbonyl group (T. D. Beeson, D. W. C. MacMillan. J. Am. Chem. Soc. 127, 8826 (2005), which is incorporated herein by reference as if fully set forth) and via the ring-opening of epoxides with a fluoride nucleophile (J. A. Kalow, A. G. Doyle. J. Am. Chem. Soc. 132, 3268 (2010), which is incorporated herein by reference as if fully set forth). A chemo-enzymatic fluorination strategy via initial P450-mediated hydroxylation (R. Fasan, A. Rentmeister, F. H. Arnold. Nat. Chem. Biol. 5, 26 (2009), which is incorporated herein by reference as if fully set forth) and a stoichiometric chemical route involving initial decarboxylation (M. Rueda-Becerril et al. J. Am. Chem. Soc. 134, ASAP (2012), which is incorporated herein by reference as if fully set forth) have also been reported. Despite this impressive progress, a method for the selective and efficient incorporation of fluorine at unactivated C—H sites within a target molecule is singularly absent in the repertoire of chemical synthesis.